Spheronized self-emulsifying system for hydrophobic and water-sensitive agents

ABSTRACT

A self-emulsifying system comprises i) microcrystalline cellulose and ii) an oily substance, surfactant, and water is useful for providing solid dosage forms of hydrophobic or water sensitive agents when dried or extruded and spheronized.

This application is a 371 of International Application NumberPCT/GB00/00150, and claims the benefit of GB 9900614.0, filed Jan. 12,1999, and GB 9915584.8, filed Jul. 2, 1999.

BACKGROUND OF THE INVENTION

The present invention relates to mixtures suitable for formulatinghydrophobic and water-sensitive active agents, these mixtures whendried, processes for producing dosage forms from the mixtures in the wetor dry states and the dosage forms themselves.

Self-emulsifying drug delivery systems have been shown to be a method ofincreasing the bioavailability of poorly water soluble active agents,such as drugs, and are an alternative to traditional formulations oflipophilic active agents.

A self-emulsifying system is a mixture of oil and surfactant which formsa fine oil-in-water emulsion when introduced into an aqueous phase underconditions of gentle agitation. Such mixtures can be used as, forexample, pharmaceutical oral drug delivery systems for lipophiliccompounds by dissolving the drug in the oil phase. The system isexpected to self-emulsify rapidly in the aqueous contents of thestomach, thereby presenting the drug in solution in small droplets ofoil. The gentle agitation required for the emulsification is provided bythe digestive motility of the stomach. Fine oil droplets should emptyrapidly from the stomach and promote wide distribution of the drugthroughout the gastrointestinal tract, thereby minimising irritationfrequently encountered with extended contact between bulk drugsubstances and the gut wall. The self-emulsifying drug delivery systemsalso provide a large interfacial area across which the drug can diffuseinto the gastrointestinal fluids. Since the drug is dissolved in the oilphase the dissolution step, which can be absorption rate limiting forpoorly water soluble drugs, is eliminated.

Several combinations of oil and surfactant have been used to produceself-emulsifying systems. The ingredients most frequently used aremedium chain triglyceride oils (vegetable oils) and nonionicsurfactants, which are acceptable for oral ingestion. Factors affectingthe efficiency of a self-emulsifying system are the HLB andconcentration of the surfactant. The dosage forms which result fromthese systems are usually either liquids or hard or soft gelatincapsules.

SUMMARY OF THE INVENTION

A self-emulsifying system comprises i) microcrystalline cellulose andii) an oily substance, surfactant, and water is useful for providingsolid dosage forms of hydrophobic or water sensitive agents when driedor extruded and spheronised.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a table (Table 1) that tabulates the quantities of liquidincorporated and the steady state extrusion force.

FIG. 2 is a table (Table 2) that tabulates the formulation number andthe size fractions.

FIG. 3 is a table (Table 3) that tabulates the results of the sizeanalysis of the formulations.

FIG. 4 is a table (Table 4) that tabulates the disintegration time forthe formulations.

FIG. 5 is a table (Table 5) that tabulates the crushing load in sizefractions.

FIG. 6 is a table (Table 6) that tabulates the shape factors for theformulation pellets.

FIG. 7 is a table (Table 7) that tabulates the surface roughness for theformulations.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a self-emulsifying system whichcomprises:

I. a first portion comprising microcrystalline cellulose; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oilysubstance;

(B) between 2 and 100%, based on the weight of the first portion, of asurfactant; and

(C) between 2 and 1000%, based on the weight of the oily substance andthe surfactants, of water;

wherein the total weight of the oily substance and the surfactant isbetween 2 and 200% of the first portion.

Microcrystalline cellulose is commercially available, for example underthe name Avicel®. The term includes, but is not limited to,pharmaceutical grade microcrystalline cellulose as defined in theBritish Pharmacopeia. Various grades of microcrystalline cellulose aredescribed in the Handbook of Pharmaceutical Excipients, 2^(e), ed. byWade and Weller, 1994, London and Washington, pages 84 to 87. As analternative to microcrystalline cellulose powdered cellulose may beused.

Again, the powdered cellulose may be, but is not limited to,pharmaceutical grade. A description of various grades can be found inthe above reference at pages 88-90.

The oily substance generally comprises a fatty acid ester or a longchain saturated, partially unsaturated or unsaturated long chainhydrocarbon. Thus the oily substance is preferably a C₁₋₂₀ ester of aC₆₋₃₀ acid or a C₂₀₋₁₀₀ hydrocarbon or a mixture thereof.

The C₆₋₃₀ acid may be naturally occurring or synthetic and generallycontains one, two, three, four or more double bonds, particularly one,two or three double bonds, and may be substituted with one or morehydroxy groups. The C₁₋₂₀ ester is the residue of a C₁₋₂₀ alcoholcomprising one, two or three hydroxy groups, which alcohol may benaturally occurring or synthetic. The acid and ester are generallylinear or branched but may contain cyclic portions.

The C₂₀₋₁₀₀ hydrocarbon is unsaturated, partially saturated orsaturated, and is preferably saturated. It may be linear or branched orcontain cyclic portions but is preferably linear. It preferably contains30-80 carbon atoms.

Examples of fatty acids include, but are not limited to, caproic acid,capric acid, caprylic acid, oleic acid, palmoic acid, stearic acid,linoleic acid, octanoic acid, decanoic acid, linolenic acid, palmiticacid, palmitoleic acid, arachidic acid, myristic acid, behenic acid andlignic acid. Mono, di and tri glycerides of these fatty acids arefavoured, in particular medium chain mono and diglycerides. Capric acidand caprylic acid are favoured. Naturally occurring vegetable oils suchas soyabean oil may be used.

Examples of C₂₀₋₁₀₀ hydrocarbon are various grades of paraffin.

The surfactant may be any known surfactant which reduces the surfacetension of the water or the oily substance thus facilitating mixing. Thesurfactant may be cationic, anionic, non-ionic or amphoteric. Aparticularly favoured surfactant is polysorbate 80, generally used at15-50% w/w. A mixture of surfactants may be used such as polysorbate 80and span 80. Span 80 is generally used at 5-25% w/w.

The amount of oily substance present is preferably up to 90%,particularly between 5 and 80%, more particularly between 10 and 50%,especially between 20 and 42% of the weight of the first portion.

The amount of surfactant present is preferably between 10 and 90%,particularly between 20 and 80%, and more particularly between 20 and50% of the weight of the first portion.

The amount of water present is preferably between 2 and 150%, morepreferably between 2 and 100%, particularly between 3 and 80%, moreparticularly between 5 and 60% and especially between 8 and 42% of theweight of oil and surfactant.

The combined weight of the second portion is preferably between 30 and95% and particularly between 35 and 95% by weight of the first portionand especially between 40 and 90%.

The precise quantities of surfactant, oily substance and water which maybe present will depend on the particular nature of these substances.

Specific combinations of oil and surfactant that may be used are: monoand diglycerides USNF (50% w/w) and polysorbate 80 NF (50% w/w); monoand diglycerides USNF (70% w/w), polysorbate 80 NF (20% w/w) and span 80(10% w/w); and soyabean oil (30%) w/w, polysorbate 80 NF (49% w/w) andspan 80 (21% w/w).

The optimal quantities for forming a dosage form, or for making amixture suitable for extrusion and spheronisation can easily bedetermined by trial and error using standard equipment. For example ifspheronised pellets are desired the mixture will be too wet if anagglomerate is obtained and will be too dry if the particlesdisintegrate during spheronisation. Nevertheless wetter or driermixtures may be suitable for drying to powders which may be used forfilling or tabletting to produce dosage forms.

In a preferred embodiment the self-emulsifying system further comprisesan active agent. The active agent may be, but is not limited to, apharmaceutical, veterinary product, agrochemical, pesticide, dye orradiochemical. In particular, it is envisaged that the self-emulsifyingsystem may be used to carry any hydrophobic or water sensitive activeagent.

In a further embodiment the first portion further comprises a filler.The filler may be any conventional filling material used in variousbranches of formulation technology, such as lactose or another sugar.Other common fillers are calcium carbonate and glyceryl monostearate.The filler may be present in an amount of 0 to 75% based on the weightof the microcrystalline cellulose, particularly 0 to 50%.

In particular the present invention is surprisingly useful for providingsolid dosage forms of hydrophobic or water sensitive active agents.

Accordingly the present invention comprises a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionallya filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oilysubstance;

(B) between 2 and 100%, based on the weight of the first portion, of asurfactant;

(C) between 2 and 1000%, based on the weight of the oily substance andthe surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance andthe surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant isbetween 2 and 200% of the first portion; which mixture is dried.

The active ingredient is preferably present in an amount of between 0.5and 50%, particularly between 2 and 40%, more particularly between 5 and25%, based on the weight of the oily substance and surfactant.

The mixture is generally dried at about room temperature to about 60°C., depending on the nature of the mixture. The drying should be donebelow a temperature causing degradation of any of the components. Dryingis generally carried out until the mixture loses no more water or atleast until the mixture is sufficiently dry to process into a soliddosage form. Drying may be carried out on a tray in an oven or byfluidised-bed drying or other conventional methods.

This drying step may be carried out before or after further processingof the mixture. If carried out before processing the dry mixture may becompressed into tablets or used to fill dosage forms.

Alternatively, before drying the mixture may be extruded by conventionalmeans, for example through a 1 mm die. The extrudate may then be driedand compressed into tablets, or spheronised by conventional means beforedrying with the resulting pellets optionally being compressed intotablets.

The present invention therefore provides a solid dosage form obtainableby drying a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionallya filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oilysubstance;

(B) between 2 and 100%, based on the weight of the first portion, of asurfactant;

(C) between 2 and 1000%, based on the weight of the oily substance andthe surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance andthe surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant isbetween 2 and 200% of the first portion.

In particular the dosage form is a tablet or filled capsule. The filledcapsule may be made of soft or hard gelatin, particularly hard gelatin.

Thus the present invention provides a process for making a solid dosageform comprising drying a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionallya filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oilysubstance;

(B) between 2 and 100%, based on the weight of the first portion, of asurfactant;

(C) between 2 and 1000%, based on the weight of the oily substance andthe surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance andthe surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant isbetween 2 and 200% of the first portion; and compressing the driedmixture into a tablet.

There is also provided a process for making a solid dosage formcomprising extruding and spheronising a mixture comprising:

I. a first portion comprising microcrystalline cellulose and optionallya filler; and

II. a second portion comprising:

(A) up to 200%, based on the weight of the first portion, of an oilysubstance;

(B) between 2 and 100%, based on the weight of the first portion, of asurfactant;

(C) between 2 and 1000%, based on the weight of the oily substance andthe surfactant, of water; and

(D) between 0.1 and 100%, based on the weight of the oily substance andthe surfactant, of an active ingredient;

wherein the total weight of the oily substance and the surfactant isbetween 2 and 200% of the first portion; drying the spheronised pelletsand either filling a capsule with the pellets or compressing the pelletsinto a tablet.

The same preferred features given above for the mixtures apply to thesolid dosage forms also.

The term “spheronised” is intended to refer to pellets which have beenprocessed on spheronisers used in the field of formulation, whether if asuitable size for laboratory or industrial scale processing, or preparedon other devices giving equivalent pellets. Such spheronisers are run atconventional speeds.

Further advantages of the present invention are that the mixture can beextruded at higher pressures than normally possible without clogging ordisintegration. Further, the extrudate readily forms spheronised pelletseven if the extrudate is prone to initial disintegration. Also thenature of the spheronised pellets is not affected by excess time on thespheroniser after they are formed. Thus the mixture shows excellenthandling properties and stability during processing. The dried mixturealso demonstrates good stability. In addition the mixtures of thepresent invention may comprise surprisingly large amounts of oilysubstance upon addition of a small quantity of water to the wet mixture.

It is understood that self-emulsifying systems other than mono anddiglycerides with polysorbate 80 may be used in the present invention,such as those disclosed in WO-A-9119563.

The following Example illustrates the present invention.

EXAMPLE

Microcrystalline cellulose (Avicel® PH 101) (FMC International, LittleIsland, Cork, Ireland) and lactose (Pharmatose® 200M) (DMVInternational, Vehgel, The Netherlands) was used as filling and pelletforming material. MP (Mono- and diglycerides USNF (50% w/w)/Polysorbate80 USNF 50% w/w). Deionized water (W) was used for preparation of MPW.

The experimental design employed in this study was a central compositedesign with two independent factors and five levels of each factor. Thisgave a total of 13 experiments, including the centre point and fourinteraction points (Podczeck, 1996). The independent factors were chosento be the ratio of lactose to Avicel® and the ratio of MP to water. Theresponses to be studied were MPW and MP content of the powder mass;extrusion force; median size, size spread, disintegration time, tensilestrength, surface roughness and shape of the pellets. The amount of MPWrequired for each batch was not known and had to be assessed by trialand error. Preliminary experiments were performed to set the limits ofthe levels of the independent factors. For the composition of the 13formulations, (Table 1: Quantities of liquid incorporated and the steadystate extrusion force). The formulations were produced in random order.

The results were analysed with univariate analysis of variance (ANOVA)to allow identification of statistically significant correlationsbetween the independent factors and the responses, using SPSS 8.0 forWindows (Podczek, 1996).

MPW mixtures were prepared by adding the MP to the water and stirringwith a magnetic stirrer for 10 minutes. The mixtures were used on thesame day as they were prepared.

Avicel® and lactose (50 g total) were pre-blended with a pestle andmortar and wetted by gradual addition of MPW. Extrusion was carried outwith a ram extruder (Lloyd MX50) with a die of 1 mm in diameter and 6 mmin length, extrusion speed 200 mm/minute. A force/displacement curve wasobtained for each extrusion to allow determination of the extrusionforce. The extrudate was spheronized for 10 minutes on a 120 mm diameterspheronizer (Caleva) using a cross-hatch friction plate with speed of1880 rpm. The resulting pellets were dried in an oven at 40° C. untilthey reached constant weight.

Size analysis was performed using a nest of British standard sieves(500, 710, 1000, 1400, 2000, 2800, 4000 and 5600 μm aperture) agitatedon a sieve shaker for 10 minutes. Retained weight data were used toconstruct cumulative % undersize distributions. Median diameter andspread was determined as the 50% value and the difference between 99%and 1%.

The disintegration of the pellets was studied in deionized water at 37°C. using a disintegration apparatus (BP 1998, modified with a 1 mm meshat the base of the tubes). Six pellets from each batch were tested. Theend point was taken as the time for disruption of the pellets.

The crushing strength of the pellets was analysed using a CT5 tester(Engineering Systems, Nottingham, UK) with a 5 kg load cell and a speedof 10 mm/minute. A random sample of 10 pellets was tested. The crushingload was converted into surface tensile stress using the followingequation (Shipway and Hutchings. 1993):

σ_(f)=(0.4F₀)/(ΠR²)

where σ_(f) is the surface tensile stress [N/m²], F is the crushing load[N] and R is the radius [m]. The radius was calculated from the Feretdiameter.

The shape of the pellets was studied by image analysis using a SeescanImage Analyser (Seescan, Cambridge, UK), completed with a black andwhite camera (CCD-4 miniature video camera module, Rengo Co. Ltd.Toyohashi, Japan) connected to a zoom lens (18-108/2.5, Olympus,Hamburg, Germany). A shape factor, to describe the roundness of thepellets, and the Feret diameter was determined by analysing a randomsample of 100 pellets from each batch. (Podczeck and Newton, 1994:Podczeck and Newton, 1995).

The surface roughness of the pellets was studied using a non-contactinglaser profilometer (UBM Microfocus Measurement System, UBM MesstechnikGmbH, Ettlingen, Germany) with a light spot diameter of 1 μm and ameasurement range of ±500 μm. The area scanned was 0.3×0.3 mm with aresolution of 1000 points/mm in both directions. Scans were levelled toremove any underlying slope or curvature. The UBSOFT (UBM MesstechnikGmbH, Ettlingen,. Germany) associated with the laser profilometer systemwas used to determine four different roughness parameters: Ra, Rq, Rtmand fractal dimension (Podezeck, 1998). Five pellets from each batch wasstudied.

The amount of MPW required for each formulation was not known and had tobe assessed by trial and error until a ‘good’ product without anyapparent agglomerates was formed. If the formulation gave agglomeratesthe amount of MPW was lowered. Some formulations gave a good product onthe first attempt. In total 25 batches were produced (Table 1). Aftersieving the ‘best’ batch from each formulation was chosen for furtheranalysis. Batches with pellets larger than 2800 μm were excluded (Table2: Retained weight (g) of pellets in the size fractions).

According to the model equation and assuming that all the waterevaporated, the maximum amount of MP that could be incorporated was 36 g(MP:water ratio 92:8, lactose:Avicel® ratio 0:100), which is 42% of drypellet weight.

Statistical analysis of the extrusion forces showed a linearrelationship with the MP:water ratio, the more MP the higher extrusionforce. The lactose:Avicel® ratio had no statistically significantinfluence. As for the spheronization process formulation number 9 seemedto have a different mechanism of spheronization than what has beenproposed (Chapman, 1985). The extrudate first broke into powder andpellets started to form after a few minutes. With many of theformulations some powder was stuck on the plate after thespheronization. This can be a problem in pharmaceutical production whenbatch after batch is loaded onto the spheronizer.

Both parameters describing the pellet size distribution, median diameterand size spread, were found to be dependent on the MP:water ratio (Table3: Results of the size analysis). The median diameter increases withincreased amount of MP and levels off. The size spread has a linearrelationship with the MP:water ratio and increases with increased amountof MP. No statistically significant correlation with the lactose:Avicel®ratio could be found.

Statistical analysis of the disintegration results showed a cubiccorrelation between disintegration time and MP:water ratio in sizefraction 1000-1400 μm, values are mean for 6 pellets (Table 4). Thedisintegration time increases dramatically when the water content isincreased from 70% to 100%. The lactose:Avicel® ratio had nostatistically significant influence (Table 5: Crushing load on pelletsin size fractions 710-1000 μm and 1000-1400 μm, values are mean of 10pellets).

The surface tensile stress was studied in two size fractions.Statistical analysis of the results showed a quadratic relationshipbetween tensile stress and the MP:water ratio for both size fractions.The lactose:Avicel® ratio had a small influence on the tensile stress insize fraction 710-1000 μm but no effect in size fraction 1000-1400 μm.Reasons for this difference could be that the pellets are formed indifferent ways or have a different composition, which could affect themechanical properties. Some of the pellets, those with a MP content of60% or more, did not snap, but were squashed between the platens. Theydeformed plastically, yet there was a yield load.

Statistical analysis of the shape factor showed that there was nostatistically significant correlation with either of the two independentfactors (Table 6: shape factors (Ecc) for the pellets in size fractions710-1000 μm and 1000-1400 μm. Values are mean of 100 pellets). Thismeans that there is no systematic change in shape as the independentfactors are varied.

The surface roughness is presented as maximum peak to Valley height forsize fraction 1000-1400 μm (Table 7). Rtm. Oneway ANOVA showed that thisparameter would be best to describe the surface roughness. Statisticalanalysis showed that Rtm was dependent on both the MP:water ratio andthe lactose:Avicel® ratio. The roughness has a minimum and according tothe model equation the smoothest pellets would be made of 100% Avicel®and MPW with 59% MP.

REFERENCES

Chapman S. R., Influence or process variables on the production ofspherical particles. Ph.D. Thesis. University of London (1985) p. 281.

Podczeck F., The development and optimization of tablet formulationsusing mathematical methods. In Alderborn G. and Nyström C., (Eds.).Pharmaceutical Powder Compaction Technology, Marcel Dekker Inc., NewYork, 1996, pp. 561-593.

Podczeck F., Particle-particle adhesion in pharmaceutical powderhandling. Imperial College Press, London, 1998, pp. 16-28.

Podczeck F. and Newton J. M., A shape factor to characterize the qualityof spheroids. J. Pharm. Pharmacol., 46 (1994) 82-85.

Podczeck F. and Newton J. M., The evaluation of a three-dimensionalshape factor for the quantitative assessment of the sphericity andsurface roughness of pellets. Int. J. Pharm., 124 (1995) 253-259.

Shipway P. H. and Hutchings I. M., Attrition of brittle spheres byfraction under compression and impact loading. Powder Technol., 76(1993) 23-30.

What is claimed is:
 1. A self-emulsifying system which comprises: I. afirst portion comprising microcrystalline cellulose; and II. a secondportion comprising: (A) up to 200%, based on the weight of the firstportion, of an oily substance; (B) between 2 and 100%, based on theweight of the first portion, of a surfactant; and (C) between 2 and1000%, based on the weight of the oily substance and the surfactants, ofwater; wherein the total weight of the oily substance and the surfactantis between 2 and 200% of the first portion.
 2. A self-emulsifying systemaccording to claim 1 wherein the amount of oily substance present isbetween 20 and 42% of the weight of the first portion.
 3. Aself-emulsifying system according to claim 1 wherein the amount ofsurfactant present is between 20 and 50% of the weight of the firstportion.
 4. A self-emulsifying system according to claim 1 wherein theamount of water present is between 8 and 42% of the weight of oil andsurfactant.
 5. A self-emulsifying system according to claim 1 whereinthe combined weight of the second portion is between 40 and 90% byweight of the first portion.
 6. A self-emulsifying system according toclaim 1 which further comprises between 0.1 and 100%, based on theweight of the oily substance and the surfactant, of an active ingredientoptionally chosen from a pharmaceutical, veterinary product,agrochemical pesticide, dye and a radiochemical.
 7. A self-emulsifyingsystem according to claim 1 wherein the first portion further comprisesa filler in an amount of 0 to 75% based on the weight of themicrocrystalline cellulose.
 8. A self-emulsifying system according toclaim 1 wherein the surfactant is polysorbate 80 or a mixture thereofwith span
 80. 9. A self-emulsifying system according to claim 1 whereinthe combination of oily substance and surfactant is mono anddiglycerides USNF (50% w/w) and polysorbate 80 NF (50% w/w); mono anddiglycerides USNF (70% w/w), polysorbate 80 NF (20% w/w) and span 80(10% w/w); or soyabean oil (30%) w/w, polysorbate 80 NF (49% w/w) andspan 80 (21% w/w).
 10. A mixture comprising: I. a first portioncomprising microcrystalline cellulose and optionally a filler; and II. asecond portion comprising: (A) up to 200%, based on the weight of thefirst portion, of an oily substance; (B) between 2 and 100%, based onthe weight of the first portion, of a surfactant; (C) between 2 and1000%, based on the weight of the oily substance and the surfactant, ofwater; and (D) between 0.1 and 100%, based on the weight of the oilysubstance and the surfactant, of an active ingredient; wherein the totalweight of the oily substance and the surfactant is between 2 and 200% ofthe first portion; which mixture is dried.
 11. The mixture of claim 10wherein the active ingredient is present in an amount of between 5 and25% based on the weight of the oily substance and surfactant.
 12. Asolid dosage form obtainable by drying a mixture comprising: I. a firstportion comprising microcrystalline cellulose and optionally a filler;and II. a second portion comprising: (A) up to 200%, based on the weightof the first portion, of an oily substance; (B) between 2 and 100%,based on the weight of the first portion, of a surfactant; (C) between 2and 1000%, based on the weight of the oily substance and the surfactant,of water; and (D) between 0.1 and 100%, based on the weight of the oilysubstance and the surfactant, of an active ingredient; wherein the totalweight of the oily substance and the surfactant is between 2 and 200% ofthe first portion.
 13. A process for making a solid dosage formcomprising drying a mixture comprising: I. a first portion comprisingmicrocrystalline cellulose and optionally a filler; and II. a secondportion comprising: (A) up to 200%, based on the weight of the firstportion, of an oily substance; (B) between 2 and 100%, based on theweight of the first portion, of a surfactant; (C) between 2 and 1000%,based on the weight of the oily substance and the surfactant, of water;and (D) between 0.1 and 100%, based on the weight of the oily substanceand the surfactant, of an active ingredient; wherein the total weight ofthe oily substance and the surfactant is between 2 and 200% of the firstportion; and compressing the dried mixture into a tablet.
 14. A processfor making a solid dosage form comprising extruding and spheronising amixture comprising: I. a first portion comprising microcrystallinecellulose and optionally a filler; and II. a second portion comprising:(A) up to 200%, based on the weight of the first portion, of an oilysubstance; (B) between 2 and 100%, based on the weight of the firstportion, of a surfactant; (C) between 2 and 1000%, based on the weightof the oily substance and the surfactant, of water; and (D) between 0.1and 100%, based on the weight of the oily substance and the surfactant,of an active ingredient; wherein the total weight of the oily substanceand the surfactant is between 2 and 200% of the first portion; dryingthe spheronised pellets and either filling a capsule with the pellets orcompressing the pellets into a tablet.